Process for preparing 1,4-dibenzodiazepines via Buchwald-Hartwig chemistry

ABSTRACT

The present application provides a one-pot catalytic process which involves the formation of 1,4-dibenzodiazepines from o-haloaldimines (either pre-formed or formed in situ) of formula (I) and o-haloanilines of formula (II) via a palladium catalyzed Buchwald-Hartwig reaction and a cyclization sequence, to afford the 1,4-dibenzodiazepine products of formula (III). The present application describes the preparation of the 1,4-dibenzodiazepine products of formula (III) from simple commercial raw materials by efficient processes.

CROSS REFERENCE TO RELATED APPLICATION

This Application is a 371 of PCT/IB2016/053685 filed on Jun. 21, 2016,which claims priority of Portuguese Application No. 108566 filed Jun.22, 2015, both of which are incorporated herein by reference.

TECHNICAL FIELD

The present application refers to a catalytic process to afford1,4-dibenzodiazepines from o-haloaldimines and o-haloanilines via apalladium catalyzed Buchwald-Hartwig reaction and what appears to be anunusual cyclization sequence.

BACKGROUND

Pharmaceuticals bearing the 1,4-dibenzodiazepine core are a veryimportant class of drugs. The first reported synthesis of adibenzodiazepine (dibenzooxazepine) was clozapine and loxapine (Hunzikeret al. 1964). Since this time other routes have been developed that relyon accessing them from their amide, lactam or other precursors (Lednicer1998 and Tsvelikhovsky and Buchwald, 2011). Some important analogueswith attractive medicinal properties, include the dibenzodiazepinones,sintamil for treating depression, diazepinomicin an antimicrobialalkaloid (Charan et al. 2004) and pirenzapine, an M1 selectiveantagonist (antimuscarinic agent), used in the treatment of pepticulcers (Yazdanian et al. 1998). Five synthetic approaches have beendeveloped to access dibenzodiazepinones (Li et al. 2014, one of themethods was retracted in 2014—Diao et al. 2011). Not many methods haverecently been described for accessing dibenzooxazepins. The method ofBuchwald and Tsvelikhovsky is particularly of note (Tsvelikhovsky andBuchwald, 2011). This method involves a Buchwald-Hartwig amination(Guram et al. 1995, Hartwig 2000, Louie and Hartwig 1995, Burke andMarques, 2015) to form the key diarylamine intermediate, followed by aPd-catalyzed ammonia cross-coupling that terminates with a ketonecondensation (Scheme 1). The reaction requires the use of 5-7equivalents of ammonia, and the yields ranged from 43-93% for 9examples. Only the tBu-DavePhos ligands provided satisfactory results,and it was suggested that the dimethylamino group present in theflanking ring is key to obtaining the desired reactivity (Lundgren andStradiotto, 2012). This method constituted the first application of thePd-Catalyzed coupling of ammonia in the synthesis of complexheterocycles. However, the reaction was carried out in two independentsteps, requiring first the preparation of the diraylamine, followed byamination with ammonia and cyclization, as illustrated in the followingscheme 1.

Thus, the present invention intends to provide a new efficient catalyticprocess which affords dibenzooxazepines in good yields.

SUMMARY

It is the goal of this application to report the development of theformation of 1,4-dibenzodiazepines from o-haloaldimines (eitherpre-formed or formed in situ) of formula (I) and o-haloanilines offormula (II) via a palladium catalyzed Buchwald-Hartwig reaction and acyclization sequence, to afford the 1,4-dibenzodiazepine products offormula (III).

The reaction yields are good, and the process is overall verysustainable and atom-economical, its principle advantage is its inherentcapacity for product structural diversity generation, and thus hasimmense potential for preparing multiple-libraries of interesting anduseful biologically active molecules.

The imine substrates used in the process are prepared (or generated insitu) from simple commercial raw materials by efficient processes, someof which are catalytic themselves. The cyclization reactions can be runat temperatures of between 50° C. and 130° C. using a variety ofcatalysts. These reactions are Pd catalyzed, the union of the metalcomplex with the ligand—generally a phosphane like, PPh₃, SPhos, XPhosor XantPhos, etc) forms the active catalyst which interacts with thesubstrate.

Loadings of between 0.1 and 5 mol % of the metal complex can be used.The mechanism is not known for sure, but there are strong indicationsthat there is first a Buchwald-Hartwig coupling reaction between theimine and the o-haloaniline to give a diarylaminoimine that undergoes ahitherto unknown N-arylation with expulsion of the arylsulfonyl unitprior or after this ring-closure event (Peixoto et al. 2015).

In this context, the present application describes a novel process forthe catalytic synthesis of 1,4-dibenzodiazepines from simple precursors,in other words, the substrates of formula (I) and formula (II) reactunder catalytic conditions to give products of formula (III) comprisingthe use of a suitable metal catalyst, wherein the reaction is conductedby adding the palladium pre-catalyst from an appropriate metal complexlike, Pd(OAc)₂, PEPPSI-iPr, PdCl₂(dppf), Pd(PPh₃)₄ in the presence of abase.

In an embodiment, the preformed catalyst is prepared by adding theligand to the metal complex in a suitable dry solvent, under an inertatmosphere and allowing the mixture to stir up to 24 h, in a temperaturerange from 50 to 130° C.

In another embodiment, the pre-catalyst used is selected from the groupcomprising Pd based metal complexes.

In another embodiment, the reaction solvent used is selected from thegroup comprising: THF, toluene, benzene, dimethyl ether, 1,4-dioxane,dichloromethane, acetonitrile, chloroform, DMF, DMA and NMP.

In yet another embodiment, the ligand used is selected from the groupcomprising monophosphane type ligands, like; triphenylphosphane,CyJohnPhos, SPhos, RuPhos, PCy₃, P(nBu)₃ and P(t-Bu)₃.

The ligand loading ranges from within 0.25 to 10 mol %.

In another embodiment, the reactions are run under an inert atmosphere(e.g. under dry nitrogen or argon).

In yet another embodiment, the reaction temperature ranges between 50°and 130° C.

GENERAL DESCRIPTION

The present application provides a catalytic process that involveso-haloaldimines and o-haloanilines that gives 1,4-dibenzodiazepinesunder palladium catalysis.

The substrates can be described by the formulae (I) and (II),

in which

X represents a halogen like, Br, Cl, I, or a triflate group (OTf),

R represents, an alkyl or aryl group,

R¹ and R³ represent a hydrogen, a saturated alkyl, allyl, vinyl orcycloalkyl group, or an aryl group, or an OH, tiol, amino, nitro, cyano,aldehyde, ketone, ester, thioester, carboxylic acid, carbamate, ether ora thioeter group,

R² represents a hydrogen, an alkyl, allyl, vinyl or aryl group,

the N in both the formulae (I) and (II), can vary position between 3 and6 in (I), considering position-1 to be the carbon attached to the iminogroup and 3 and 6 in (I), considering position-1 to be the carbonattached to the imino group, and between 3 and 6 in (II), consideringposition-1 to be the carbon attached to the amino group 6 in (II).

The sulfonylimine substrates of formula (I) are obtained from thecorresponding aldehydes (Weinreb, 1997) using common literature methods.Bromide, chloride or iodide precursors can be used, with a preferencefor the cheaper bromides. Substrates of formula (II) are commerciallyavailable.

The reactions are normally conducted by simply adding the pre-catalystand ligand the sulfonylimine substrates of formula (I) and the anilinesof formula (II) to a flask under an inert gas atmosphere in the presenceof a base like; triethylamine, K₂CO₃, Na₂CO₃, CaCO₃, Ba(OH)₂, KOAc,DIPA, K₃PO₄, NMM, DBU, KOH, KF, Cs₂CO₃, and KOtBu.

The quantity of base used ranged from 1 to 5 equivalents.

With regard to the ligands used, these were generally commercialmonophosphanes, (like; triphenylphosphane, CyJohnPhos, SPhos, RuPhos,PCy₃, P(nBu)₃ and P(t-Bu)₃.

The ligand loading ranges from within 0.25 to 10 mol %.

The palladium complexes that were used were generally: Pd(OAc)₂,PEPPSI-iPr catalyst, Pd₂(dba)₃.CHCl₃, [Pd(TFA)₂], PdCl₂(dppf),Pd(PPh₃)₄, cationic palladium (II) complexes and Pd—NHCs.

The following reaction solvents can be used: toluene, dimethyl ether,diethyl ether, 1,4-dioxane, dichloromethane, acetonitrile, chloroform,DMF, DMA and NMP.

The reactions were run under an inert atmosphere (e.g. under drynitrogen or argon).

For the aforementioned catalytic reaction, 0.1-5 mol % of themetal-complex is required relative to the substrate.

The reactions are generally run at temperatures of between 50° C. and130° C. using a variety of chiral catalysts or non-chiral catalysts.Yields of up to 85% can be achieved. The reaction times varied frombetween 15 and 24 hours.

EXAMPLES

General Catalytic Procedure for the Synthesis of Dibenzodiazepines

The reactions were performed under a nitrogen atmosphere using aRadleys® 12 position carousel reactor station. Pd(OAc)₂ (2.5 mol %),SPhos (5.0 mol %), o-bromoarylimines, o-bromoarylamines, Cs₂CO₃ (2equivs) and THF were added to the reaction tube. The reactions wereperformed at 100° C. for 18 h. The reactions were monitored by TLC, tofollow the disappearance of the starting materials. After completion,the mixture was allowed to cool to room temperature. The reactionmixture was filtered with celite and the solvent removed under reducedpressure and then purified by column chromatography using 9:1Hexane/EtOAc, to give the following pure compounds 1-11.

5H-Dibenzo[b,e][1,4]diazepine): FromN-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and2-bromoaniline (0.258 g), according to the general procedure, the titlecompound was obtained as a yellow solid (0.20 g, 70%) m.p. 124.0-124.5°C. ¹H NMR (400 MHz, CDCl₃): δ 7.06-7.12 (m, 2H, ArH), 7.33-7.37 (m, 2H,ArH), 7.42-7.46 (m, 1H, ArH), 7.62-7.66 (m, 2H, ArH), 8.33 (dd, J=6.6and 2.0 Hz, 1H, ArH), 8.76 (br s, 1H, HC═N) ppm. ¹³C NMR (100 MHz,CDCl₃): δ 118.5 (C), 120.0 (CH), 126.3 (C), 127.2 (CH), 128.0 (CH),128.5 (CH), 129.7 (CH), 133.0 (CH), 133.2 (CH), 133.4 (CH), 134.4 (C),150.5 (C), 160.8 (HC═N) ppm. MS (ESI− TOF) m/z: 195.2 (M⁺+H).

2-Fluoro-5H-dibenzo[b,e][1,4]diazepine: FromN-(2-bromo-5-fluorobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.3mmol) and 2-bromoaniline (0.224 g), according to the general procedure,the title compound was obtained as a yellow solid (0.40 g, 76%) m.p.107.2-108.8° C. ¹H NMR (400 MHz, CDCl₃): δ 7.05-7.14 (m, 3H, ArH),7.34-7.38 (m, 1H, ArH), 7.58-7.67 (m, 2H, ArH), 8.03-8.06 (m, 1H, ArH),8.70 (br s, 1H, HC═N) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 116.0 (d, J=24Hz, CH), 118.7 (C), 119.8 (CH), 120.2 (d, J=23 Hz, CH), 127.6 (CH),128.6 (CH), 133.3 (CH), 134.6 (d, J=7.5 Hz, CH), 136.3 (C), 146.1 (C),150.0 (C), 159.6 (HC═N), 162.3 (d, J=239.7 Hz, C—F) ppm. MS (ESI− TOF)m/z: 213.21 (M⁺+H).

2-Methoxy-5H-dibenzo[b,e][1,4]diazepine: FromN-(2-bromo-5-methoxybenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.4mmol) and 2-bromoaniline (0.241 g), according to the general procedurethe title compound was obtained as a brown semi-solid (0.222 g, 76%). ¹HNMR (400 MHz, CDCl₃): δ 3.87 (s, 3H, OMe), 6.91-6.94 (m, 1H, ArH),7.04-7.10 (m, 2H, ArH), 7.31-7.35 (m, 1H, ArH), 7.47-7.49 (m, 1H, ArH),7.62-7.64 (m, 1H, ArH), 7.84-7.85 (m, 1H, ArH), 8.69 (br s, 1H, HC═N)ppm. ¹³C NMR (100 MHz, CDCl₃): δ 55.8 (OMe), 118.0 (CH), 119.9 (CH),120.7 (CH), 127.2 (CH), 128.4 (C), 128.5 (CH), 132.6 (C), 133.1 (CH),133.9 (CH), 134.0 (C), 134.8 (C), 150.2 (C), 160.6 (HC═N) ppm. MS (ESI−TOF) m/z: 225.27 (M⁺+H).

3-Methoxy-5H-dibenzo[b,e][1,4]diazepine: FromN-(2-bromo-4-methoxybenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.4mmol) and 2-bromoaniline (0.241 g), according to the general procedurethe title compound was obtained as a brown solid/oil (0.218 g, 75%). ¹HNMR (400 MHz, CDCl₃): δ 3.87 (s, 3H, OMe), 6.95-7.08 (m, 3H, ArH),7.31-7.35 (m, 1H, ArH), 7.62-7.64 (m, 1H, ArH), 7.89-7.91 (m, 1H, ArH),8.27-8.29 (m, 1H, ArH), 8.66 (br s, 1H, HC═N) ppm. ¹³C NMR (100 MHz,CDCl₃): δ 55.9 (OMe), 114.6 (CH), 118.1 (CH), 120.0 (CH), 124.9 (CH),126.8 (C), 128.5 (CH), 128.9 (C), 130.6 (CH), 131.0 (C), 132.6 (C),133.2 (CH), 156.8 (C), 159.9 (HC═N) ppm. MS (ESI− TOF) m/z: 225.27(M⁺+H).

3-Methoxy-5H-dibenzo[b,e][1,4]diazepin-2-ol: FromN-(2-bromo-5-hydroxy-4-methoxybenzylidene)-4-methylbenzenesulfonamide(0.50 g, 1.3 mmol) and 2-bromoaniline (0.224 g), according to thegeneral procedure the title compound was obtained as a colorless oil(0.225 g, 72%). ¹H NMR (400 MHz, CDCl₃): δ 3.96 (s, 3H, OMe), 4.06 (brs, 1H, OH), 5.68 (br s, 1H, NH), 7.03-7.09 (m, 3H, ArH), 7.31-7.35 (m,1H, ArH), 7.62-7.64 (m, 1H, ArH), 7.91 (s, 1H, ArH), 8.62 (br s, 1H,HC═N) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 56.5 (OMe), 114.5 (CH), 114.9(CH), 120.0 (CH), 127.0 (CH), 128.5 (CH), 132.7 (C), 133.3 (CH), 144.2(C), 145.5 (C), 150.3 (C), 150.6 (C), 151.8 (C), 160.1 (HC═N) ppm. MS(ESI− TOF) m/z: 241.27 (M⁺+H).

8-(Trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine: FromN-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and2-bromo-4-(trifluoromethyl)aniline (0.360 g), according to the generalprocedure the title compound was obtained as a yellow semi-solid (0.178g, 46%). ¹H NMR (400 MHz, CDCl₃): δ 7.10-7.12 (m, 1H, ArH), 7.37-7.46(m, 2H, ArH), 7.59-7.67 (m, 2H, ArH), 7.90 (br s, 1H, ArH), 8.30-8.33(m, 1H, ArH), 8.62 (br s, 1H, HC═N) ppm. ¹³C NMR (100 MHz, CDCl₃): δ125.7 (q, J=7.0 Hz, CH), 126.6 (CH), 127.3 (CH), 129.7 (q, J=260.0 Hz,CF₃), 129.2 (C), 130.0 (q, J=3.8 Hz, CH), 130.3 (q, J=6.8 Hz, CH), 132.1(q, J=30.0 Hz, C—CF₃), 133.7 (CH), 133.9 (CH), 147.1 (C), 153.7 (C),158.0 (C), 162.2 (HC═N) ppm. MS (ESI− TOF) m/z: 263.24 (M⁺+H).

7-Methyl-5H-dibenzo[b,e][1,4]diazepine: FromN-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and2-bromo-5-methylaniline (0.279 g), according to the general procedurethe title compound was obtained as a white oil (0.203 g, 65%). ¹H NMR(400 MHz, CDCl₃): δ 2.36 (s, 3H, CH₃), 6.86-6.93 (m, 2H, ArH), 7.32-7.36(m, 1H, ArH), 7.41-7.46 (m, 1H, ArH), 7.49.7.51 (m, 1H, ArH), 7.62-7.67(m, 1H, ArH), 8.30-8.33 (m, 1H, ArH), 8.74 (br s, 1H, HC═N) ppm. MS(ESI− TOF) m/z: 209.27 (M⁺+H).

7-Nitro-5H-dibenzo[b,e][1,4]diazepine (4ad): FromN-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and2-bromo-5-nitroaniline (0.326 g), according to the general procedure thetitle compound was obtained as a yellow solid (0.215 g, 60%) m.p.139.3-139.7° C. ¹H NMR (400 MHz, CDCl₃): δ 7.40-7.46 (m, 2H, ArH), 7.67(dd, J=1.2 and 8.0 Hz, 1H, ArH), 7.82 (d, J=8.8 Hz, ArH), 7.89 (d, J=2.8Hz, ArH), 7.96 (dd, J=2.8 and 8.8 Hz, ArH), 8.31 (dd, J=1.2 and 8.0 Hz,ArH), 8.82 (br s, 1H, HC═N) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 114.6 (CH),121.3 (CH), 126.0 (C), 126.8 (C), 128.1 (CH), 129.8 (CH), 133.6 (CH),133.7 (C), 133.8 (CH), 133.9 (CH), 148.1 (C), 151.5 (C), 162.8 (HC═N)ppm. MS (ESI− TOF) m/z: 240.23 (M⁺+H).

5H-dibenzo[b,e][1,4]diazepine-7-carbonitrile: FromN-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.25 g, 0.74 mmol)and 3-amino-4-bromobenzonitrile (0.146 g), according to the generalprocedure, the title compound was obtained as a yellow semi-solid (0.085g, 53%). ¹H NMR (400 MHz, CDCl₃): δ 3.68 (br s, 1H, NH), 7.11 (d, J=8.0Hz, ArH), 7.38-7.48 (m, 2H, ArH), 7.63-7.67 (m, 2H, ArH), 7.93 (d, J=1.6Hz, ArH), 8.29 (dd, J=2.0 and 7.8 Hz, ArH), 8.74 (br s, 1H, HC═N) ppm.¹³C NMR (100 MHz, CDCl₃): δ 110.5 (C), 117.7 (C), 118.3 (C), 120.6 (CH),126.7 (C), 128.1 (CH), 129.8 (CH), 132.5 (CH), 133.6 (CH), 133.7 (C),133.8 (CH), 136.6 (CH), 154.7 (C), 162.5 (HC═N) ppm.

8-Fluoro-6-methyl-5H-dibenzo[b,e][1,4]diazepine: FromN-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and2-bromo-4-fluoro-6-methylaniline (0.304 g), according to the generalprocedure, the title compound was obtained as a yellow solid (0.251 g,74%) m.p. 78.4-79.0° C. ¹H NMR (400 MHz, CDCl₃): δ 2.22 (s, 3H, CH₃),6.69-6.95 (m, 1H, ArH), 7.21-7.23 (m, 1H, ArH), 7.36-7.45 (m, 2H, ArH),7.54-7.66 (m, 1H, ArH), 8.27-8.29 (m, 1H, ArH), 8.67 (br s, 1H, HC═N)ppm. ¹³C NMR (100 MHz, CDCl₃): δ 29.8 (CH₃), 116.6 (d, J=21.7 Hz, CH),117.6 (d, J=24.9 Hz, CH), 126.2 (C), 128.0 (CH), 129.2 (CH), 131.5 (C),133.1 (CH), 133.4 (CH), 134.3 (C), 138.5 (C), 146.5 (C), 159.0 (d,J=244.7 Hz, C—F), 165.1 (HC═N) ppm. MS (ESI− TOF) m/z: 227.26 (M⁺+H).

8-Fluoro-2-methoxy-6-methyl-5H-dibenzo[b,e][1,4]diazepine):

From N-(2-bromo-5-methoxybenzylidene)-4-methylbenzenesulfonamide (0.50g, 1.4 mmol) and 2-bromo-4-fluoro-6-methylaniline (0.276 g), accordingto the general procedure the title compound was obtained as a yellowsolid (0.216 g, 62%) 68.5-69.2° C. ¹H NMR (400 MHz, CDCl₃): δ 2.22 (s,3H, CH₃), 3.88 (s, 3H, OMe). 6.91.6.98 (m, 2H, ArH), 7.21-7.24 (m, 1H,ArH), 7.51-7.53 (m, 1H, ArH), 7.80-7.81 (m, 1H, ArH), 8.63 (br s, 1H,HC═N) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 19.3 (CH₃), 55.9 (OMe), 112.4(CH), 116.5 (d, J=21.7 Hz, CH), 117.1 (C), 117.4 (d, J=26.9 Hz, CH),120.8 (CH), 123.4 (C), 131.5 (d, J=8.2 Hz, C), 134.1 (CH), 134.7 (d,J=3.1 Hz, C), 146.4 (C), 159.0 (d, J=244.6 Hz, C—F), 159.3 (C), 165.0(HC═N) ppm. MS (ESI− TOF) m/z: 257.28 (M⁺+H).

Naturally, the present application is by no means restricted to theembodiments described in this document, and a person with average skillsin the art might predict many possibilities of altering the same withoutdeparting from the general idea, as defined in the claims.

Accordingly, the scope of the present application is to be construed inaccordance with the substance defined by the following claims.

Abbreviations

-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DIPA Diisopropylamine-   DMA Dimethylacetamide-   NHC N-Heterocyclic Carbene-   NMM N-Methylmorpholine-   NMP N-Methylpiperidine-   PEPPSI catalyst Pyridine-Enhanced Precatalyst Preparation    Stabilization and Initiation-   SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-   TBAAc Tetrabutylammonium acetate-   Tf Triflate (trifluoromethylsulfonyl)-   TFA Trifluoroacetic acid-   XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene-   XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

REFERENCES

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The invention claimed is:
 1. A process for the catalytic one-potsynthesis of products of formula (III) from substrates of formula (I)and (II) respectively,

wherein, X represents a halogen group or a triflate group (OTf); Rrepresents, an alkyl or aryl group; R¹ and R³ represent a hydrogen, asaturated alkyl, allyl, vinyl or cycloalkyl group, or an aryl group, oran OH, tiol, amino, nitro, cyano, aldehyde, ketone, ester, thioester,carboxylic acid, carbamate, ether or a thioeter group; R² represents ahydrogen, an alkyl, allyl, vinyl or aryl group; comprising the use of anactive palladium catalyst, at a loading of between 0.1 and 5 mol %,wherein the reaction is conducted by adding a palladium complex, aligand at a loading of between 0.25 and 10 mol %, and a base in asolvent.
 2. The process according to claim 1, wherein the activecatalyst is prepared by adding the ligand to the palladium complex in adry solvent, under an inert atmosphere and allowing the mixture to stirup to 24 h with a temperature range from 50 to 130° C.
 3. The processaccording to claim 1, wherein the palladium complex used is selectedfrom the group consisting of Pd(OAc)₂, PEPPSI-iPr catalyst,Pd₂(dba)₃.CHCl₃, [Pd(TFA)₂], PdCl₂(dppf), Pd(PPh₃)₄, cationic palladium(II) complexes and Pd—NHCs.
 4. The process according to claim 1, whereinthe reaction solvent used is selected from the group consisting of:toluene, dimethyl ether, diethyl ether, 1,4-dioxane, acetonitrile,chloroform, DMF, DMA and NMP.
 5. The process according to claim 1,wherein the ligand is a monophosphane type ligand.
 6. The processaccording to claim 1, wherein the base is selected from the groupconsisting of triethylamine, K₂CO₃, Na₂CO₃, CaCO₃, Ba(OH)₂, KOAc, DIPA,K₃PO₄, NMM, DBU, KOH, KF, Cs₂CO₃, and KOtBu.
 7. The process according toclaim 1, wherein the substrate of formula (I) is pre-formed or formed insitu.
 8. The process according to claim 1, wherein the reaction is rununder an inert atmosphere.
 9. The process according to claim 1, whereinthe reaction temperature ranges between 50 and 130° C.
 10. The processaccording to claim 1, wherein the halogen group is selected from thegroup consisting of Br, Cl and I.